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As palliative care (PC) moves upstream in the course of advanced illness, it is critical that PC providers have a broad understanding of curative and palliative treatments for serious diseases. Possessing a working knowledge of radiation therapy (RT), one of the three pillars of cancer care, is crucial to PC providers given RT's role in both the curative and palliative settings. This article provides PC providers with a primer on the vocabulary of RT; the team of people involved in the planning of RT; and common indications, benefits, and side effects of treatment.

Purpose: The purpose of this study was to assess the state of palliative and supportive care (PSC) and palliative radiation therapy (RT) educational curricula in radiation oncology residency programs in the United States., Methods and Materials: We surveyed 87 program directors of radiation oncology residency programs in the United States between September 2015 and November 2015. An electronic survey on PSC and palliative RT education during residency was sent to all program directors. The survey consisted of questions on (1) perceived relevance of PSC and palliative RT to radiation oncology training, (2) formal didactic sessions on domains of PSC and palliative RT, (3) effective teaching formats for PSC and palliative RT education, and (4) perceived barriers for integrating PSC and palliative RT into the residency curriculum., Results: A total of 57 responses (63%) was received. Most program directors agreed or strongly agreed that PSC (93%) and palliative radiation therapy (99%) are important competencies for radiation oncology residents and fellows; however, only 67% of residency programs had formal educational activities in principles and practice of PSC. Most programs had 1 or more hours of formal didactics on management of pain (67%), management of neuropathic pain (65%), and management of nausea and vomiting (63%); however, only 35%, 33%, and 30% had dedicated lectures on initial management of fatigue, assessing role of spirituality, and discussing advance care directives, respectively. Last, 85% of programs reported having a formal curriculum on palliative RT. Programs were most likely to have education on palliative radiation to brain, bone, and spine, but less likely on visceral, or skin, metastasis., Conclusions: Residency program directors believe that PSC and palliative RT are important competencies for their trainees and support increasing education in these 2 educational domains. Many residency programs have structured curricula on PSC and palliative radiation education, but room for improvement exists in management of fatigue, assessing role of spirituality, and discussion regarding advance care planning., (Copyright © 2016 American Society of Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: Bilobar colorectal liver metastases (CRLM), are now aggressively managed in a multidisciplinary fashion with a two-stage hepatectomy; however, up to 30% of patients are not candidates for second stage hepatectomy. In this report, we describe a novel technique of delivering ablative radiation to the entire right hemiliver by using proton therapy in a series of patients., Methods: A data base of patients undergoing entire right hemiliver ablative radiation was maintained prospectively. Clinical, pathologic and treatment characteristics were collected for these patients. Survival duration was calculated from end of radiation. Radiation was delivered with proton therapy using deep inspiratory breath hold (DIBH) and a phase contrast simulation CT scan., Results: All five patients tolerated radiation treatment well. All four patients treated with biologic equivalent dose (BED) >89.6 Gy achieved partial or complete radiographic response and in-field local control at last follow up. Two patients are alive and without evidence of disease. Two patients experienced disease progression outside of the liver., Conclusion: These results suggest that the use of stereotactic proton therapy as a salvage therapy for patients with CRLM not amenable to second stage hepatectomy may achieve good local control and permit an opportunity for long term survival., (Copyright © 2016. Published by Elsevier Inc.)

Purpose: To review acute and late toxicities after chemoradiation for locally advanced pancreatic ductal adenocarcinoma in patients who were treated with escalated dose radiation (EDR)., Methods and Materials: Maximum Common Terminology Criteria for Adverse Events Version 4.0 acute toxicities (AT) during radiation and within 60 days after radiation were recorded for both acute gastrointestinal toxicity and overall toxicity (OT). Late toxicities were also recorded. EDR was generally delivered with daily image guidance and breath-hold techniques using intensity modulated radiation therapy (IMRT) planning. These were compared with patients who received standard dose radiation (SDR) delivered as 50.4 Gy in 28 fractions using 3-dimensional chemoradiation therapy planning., Results: A total of 59 of 154 patients (39%) received EDR with biologically equivalent doses >70 Gy. The most frequent schedules were 63 Gy in 28 fractions (19 of 154 patients), 67.5 Gy in 15 fractions (10 of 154 patients), and 70 Gy in 28 fractions (15 of 154 patients). No grade 4 or grade 5 OT or late toxicities were reported. Rates of grade 3 acute gastrointestinal toxicity were significantly lower in patients who received EDR compared with SDR (1% vs 14%; P < .001). Similarly, rates of grade 3 OT were also lower for EDR compared with SDR (4% vs 16%; P = .004). The proportion of patients who experienced no AT was higher in the EDR group than the SDR group (36% vs 15%; P = .001). For EDR patients treated with IMRT, a lower risk of AT was associated with a later treatment year ( P = .007), nonpancreatic head tumor location ( P = .01), breath-hold ( P = .002), 4-dimensional computed tomography ( P = .003), computed tomography on rails ( P = .002), and lower stomach V40 ( P = .03). With a median time of 12 months (range, 1-79 months) from the start of radiation therapy to the last known follow-up in the EDR group, 51 of 59 patients (86%) had no late toxicity. Six of 59 EDR patients (10%) had either strictures or gastrointestinal bleeding that required intervention. No significant predictors of late toxicity were identified., Conclusion: Overall acute and late toxicity rates were low with EDR using an IMRT technique with image guidance and respiratory gating.

Background: Genetic markers for distant metastatic disease in patients with colorectal cancer (CRC) are not well defined. Identification of genetic alterations associated with metastatic CRC could help to guide systemic and local treatment strategies. We evaluated the association of tumor necrosis factor receptor superfamily member 10C (TNFRSF10C) copy number variation (CNV) with distant metastatic disease in patients with CRC using The Cancer Genome Atlas (TCGA)., Methods: Genetic sequencing data and clinical characteristics were obtained from TCGA for all available patients with CRC. There were 515 CRC patient samples with CNV and clinical outcome data, including a subset of 144 rectal adenocarcinoma patient samples. Using the TCGA CRC dataset, CNV of TNFRSF10C was evaluated for association with distant metastatic disease (M1 vs. M0). Multivariate logistic regression analysis with odds ratio (OR) using a 95% confidence interval (CI) was performed adjusting for age, T stage, N stage, adjuvant chemotherapy, gender, microsatellite instability (MSI), location, and surgical margin status., Results: TNFRSF10C CNV in patients with CRC was associated with distant metastatic disease [OR 4.81 (95% CI, 2.13-10.85) P<0.001] and positive lymph nodes [OR 18.83 (95% CI, 8.42-42.09)]; P<0.001) but not MSI (OR P=0.799). On multivariate analysis, after adjusting for pathologic T stage, N stage, adjuvant chemotherapy, gender, and MSI, TNFRSF10C CNV remained significantly associated with distant metastatic disease (OR P=0.018). Subset analysis revealed that TNFRSF10C CNV was also significantly associated with distant metastatic disease in patients with rectal adenocarcinoma (OR P=0.016)., Conclusions: TNFRSF10C CNV in patients with CRC is associated with distant metastatic disease. With further validation, such genetic profiles could be used clinically to support optimal systemic treatment strategies versus more aggressive local therapies in patients with CRC, including radiation therapy for rectal adenocarcinoma.

Purpose: The accuracy of abdominal magnetic resonance imaging (MRI) in measuring gross tumor volume in patients with resectable cholangiocarcinoma (CC) is unknown. CC is a highly difficult tumor to visualize and treatment with dose-escalated radiation therapy requires clear tumor delineation. We aim to investigate the concordance between imaging and pathologic size in patients with resected CC to determine the usefulness of MRI for image guided treatment modalities., Methods and Materials: The records of 51 patients with resected CC who underwent preoperative MRI were evaluated. Each preoperative MRI was individually reviewed by a diagnostic radiologist (P.M.), who was blinded to pathologic measurements. A combination of dynamic multiphase contrast-enhanced T1- and T2-weighted images, original imaging reports, and pathologic reports were reviewed for greatest tumor dimensions. A general linear regression model was used to examine the outcome MRI minus pathology using MRI report, T1-weighted measurement, or T2-weighted measurement. A multivariable regression model was fit to assess the association of other factors with pathologic underestimation., Results: The median age was 69 years. Eleven tumors were categorized distal/extrahepatic, 17 hilar, and 23 intrahepatic CC. The median tumor size on pathology report was 3.00 cm (range, 0.3-19). The median tumor size from the MRI report was 3 cm (range, 0.80-16.20) and median tumor size on independent radiological review was 3 cm (range, 0.90-17) on the T1-weighted and 3 cm (range, 0.90-17) on the T2-weighted MRI sequences. When compared with pathologic tumor size, the MRI report dimension was found to underestimate tumor size by 4.1 mm (P = .04). On multivariable analysis, pathologic size underestimation was influenced by increasing tumor size (slope, -0.20; P < .001); however, underestimation was not affected by tumor location or MRI sequence., Conclusions: MRI underestimates tumor size, which was more pronounced with larger tumors, but not influenced by tumor location. The potential for gross tumor volume underestimation should be considered when planning highly conformal radiation therapy treatment of CC., (Copyright © 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Pancreatic cancer is one of the deadliest cancers with a very poor prognosis. Recently, there has been a significant increase in research directed towards identifying potential biomarkers that can be used to diagnose and provide prognostic information for pancreatic cancer. These markers can be used clinically to optimize and personalize therapy for individual patients. In this review, we focused on 3 biomarkers involved in the DNA damage response pathway and the necroptosis pathway: Chromodomain-helicase-DNA binding protein 5, chromodomain-helicase-DNA binding protein 7, and mixed lineage kinase domain-like protein. The aim of this article is to review present literature provided for these biomarkers and current studies in which their effectiveness as prognostic biomarkers are analyzed in order to determine their future use as biomarkers in clinical medicine. Based on the data presented, these biomarkers warrant further investigation, and should be validated in future studies.

Background: Gastric adenocarcinoma (GAC) is one of the most commonly diagnosed cancers worldwide. Two standard approaches for treatment of resectable GAC include adjuvant 5-fluorouracil-based chemoradiotherapy [per Intergroup 0116 (INT-0116) trial and perioperative epirubicin, cisplatin, fluorouracil (ECF) chemotherapy per Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial]. Controversy remains regarding the most appropriate treatment strategy to decrease recurrence rates and improve survival following surgery. The purpose of this study was to analyze how patterns of care for patients with GAC treated at Emory University Hospital changed following publication of the MAGIC trial in 2006., Methods: We analyzed a prospectively maintained database of 150 patients who underwent resection for GAC between December 2000 and June 2013. Patients were divided into two cohorts, Early [2000-2006] and late [2007-2013]. The primary objective was to compare the number of patients assigned to adjuvant chemoradiotherapy (aCRT) vs. perioperative chemotherapy (PC) throughout the study period and secondarily assess for recurrence patterns and survival outcomes for patients assigned to those two strategies., Results: Between 2000 and 2013, 124 patients received adjuvant therapy for GAC. Fifty-four patients were treated with PC and 70 patients with aCRT. The early cohort included 56 patients, and the late cohort included 94 patients. There was no statistical difference in the number of patients receiving aCRT between the Early and Late cohorts [n=23 (50%) vs. 35 (38%) respectively, P=0.21]. PC increased from 2 patients (3.6%) in the Early cohort to 32 patients (34%) in the Late cohort (P<0.001). Four-year overall survival (OS) was 32.6% for the Early cohort and 68.8% for the Late cohort (P=0.010). Overall recurrence rate was 25.3% with no significant difference in rates of recurrence seen between the Early and Late cohorts., Conclusions: PC has become more prevalent in patients treated at Emory following publication of the MAGIC trial in 2006. OS, but not recurrence rates, has also improved since publication. Although improved survival is suggestive of improved care, the question of optimal treatment regimen remains open. Further prospective comparisons of PC and aCRT are needed to identify patient and disease parameters that may guide therapy selection.

Purpose: To evaluate nuclear hypoxia-inducible factor 1α (HIF-1α) expression as a prognostic factor for distant recurrence (DR) and local recurrence (LR) after pancreatic adenocarcinoma resection., Methods and Materials: Tissue specimens were collected from 98 patients with pancreatic adenocarcinoma who underwent resection without neoadjuvant therapy between January 2000 and December 2011. Local recurrence was defined as radiographic or pathologic evidence of progressive disease in the pancreas, pancreatic bed, or associated nodal regions. Distant recurrence was defined as radiographically or pathologically confirmed recurrent disease in other sites. Immunohistochemical staining was performed and scored by an independent pathologist blinded to patient outcomes. High HIF-1α overall expression score was defined as high percentage and intensity staining and thus score >1.33. Univariate analysis was performed for HIF-1α score with LR alone and with DR. Multivariate logistic regression was used to determine predictors of LR and DR., Results: Median follow-up time for all patients was 16.3 months. Eight patients (8%) demonstrated isolated LR, 26 patients (26.5%) had isolated DR, and 13 patients had both LR and DR. Fifty-three patients (54%) had high HIF-1α expression, and 45 patients (46%) had low HIF-1α expression. High HIF-1α expression was significantly associated with DR (P=.03), and low HIF-1α expression was significantly associated with isolated LR (P=.03). On multivariate logistic regression analysis, high HIF-1α was the only significant predictor of DR (odds ratio 2.46 [95% confidence interval 1.06-5.72]; P=.03). In patients with a known recurrence, an HIF-1α score ≥2.5 demonstrated a specificity of 100% for DR., Conclusions: High HIF-1α expression is a significant predictor of distant failure versus isolated local failure in patients undergoing resection of pancreatic adenocarcinoma. Expression of HIF-1α may have utility in determining candidates for adjuvant local radiation therapy and systemic chemotherapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The DNA damage response (DDR) promotes genome integrity and serves as a cancer barrier in precancerous lesions but paradoxically may promote cancer survival. Genes that activate the DDR when dysregulated could function as useful biomarkers for outcome in cancer patients. Using a siRNA screen in human pancreatic cancer cells, we identified the CHD5 tumor suppressor as a gene, which, when silenced, activates the DDR. We evaluated the relationship of CHD5 expression with DDR activation in human pancreatic cancer cells and the association of CHD5 expression in 80 patients with resected pancreatic adenocarcinoma (PAC) by immunohistochemical analysis with clinical outcome. CHD5 depletion and low CHD5 expression in human pancreatic cancer cells lead to increased H2AX-Ser139 and CHK2-Thr68 phosphorylation and accumulation into nuclear foci. On Kaplan-Meier log-rank survival analysis, patients with low CHD5 expression had a median recurrence-free survival (RFS) of 5.3 vs 15.4 months for patients with high CHD5 expression (P=0.03). In 59 patients receiving adjuvant chemotherapy, low CHD5 expression was associated with decreased RFS (4.5 vs 16.3 months; P=0.001) and overall survival (OS) (7.2 vs 21.6 months; P=0.003). On multivariate Cox regression analysis, low CHD5 expression remained associated with worse OS (HR: 3.187 (95% CI: 1.49-6.81); P=0.003) in patients undergoing adjuvant chemotherapy. Thus, low CHD5 expression activates the DDR and predicts for worse OS in patients with resected PAC receiving adjuvant chemotherapy. Our findings support a model in which dysregulated expression of tumor suppressor genes that induce DDR activation can be utilized as biomarkers for poor outcome.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor outcomes with current therapies. Gemcitabine is the primary adjuvant drug used clinically, but its effectiveness is limited. In this study, our objective was to use a rationale-driven approach to identify novel biomarkers for outcome in patients with early-stage resected PDAC treated with adjuvant gemcitabine. Using a synthetic lethal screen in human PDAC cells, we identified 93 genes, including 55 genes linked to DNA damage responses (DDR), that demonstrated gemcitabine sensitization when silenced, including CHD7, which functions in chromatin remodeling. CHD7 depletion sensitized PDAC cells to gemcitabine and delayed their growth in tumor xenografts. Moreover, CHD7 silencing impaired ATR-dependent phosphorylation of CHK1 and increased DNA damage induced by gemcitabine. CHD7 was dysregulated, ranking above the 90th percentile in differential expression in a panel of PDAC clinical specimens, highlighting its potential as a biomarker. Immunohistochemical analysis of specimens from 59 patients with resected PDAC receiving adjuvant gemcitabine revealed that low CHD7 expression was associated with increased recurrence-free survival (RFS) and overall survival (OS), in univariate and multivariate analyses. Notably, CHD7 expression was not associated with RFS or OS for patients not receiving gemcitabine. Thus, low CHD7 expression was correlated selectively with gemcitabine sensitivity in this patient population. These results supported our rationale-driven strategy to exploit dysregulated DDR pathways in PDAC to identify genetic determinants of gemcitabine sensitivity, identifying CHD7 as a novel biomarker candidate to evaluate further for individualizing PDAC treatment., (©2014 American Association for Cancer Research.)

Purpose: Radiation therapy (RT) dose escalation in unresectable pancreatic adenocarcinoma (PAC) remains investigational. We examined the association between total RT dose and overall survival (OS) in patients with unresectable PAC., Methods and Materials: National cancer data base (NCDB) data were obtained for patients who underwent definitive chemotherapy and RT (chemo-RT) for unresectable PAC. Univariate (UV) and multivariate (MV) survival analysis were performed along with Kaplan-Meier (KM) estimates for incremental RT dose levels., Results: A total of 977 analyzable patients met inclusion criteria. Median tumor size was 4.0 cm (0.3-40 cm) and median RT dose was 45 Gy. Median OS was 10 months (95% CI, 9-10 months). On MV analysis RT dose <30 Gy [HR, 2.38 (95% CI, 1.85-3.07); P<0.001] and RT dose ≥30 to <40 Gy [HR, 1.41 (95% CI, 1.04-1.91); P=0.026] were associated with lower OS when compared with dose ≥55 Gy. Patients receiving RT doses from 40 to <45, 45 to <50, 50 to <55, and ≥55 Gy did not differ in OS., Conclusions: Lack of benefit to OS with conventionally delivered RT above 40 Gy is shown. Optimal RT dose escalation methods in unresectable PAC remain an important subject for investigation in prospective clinical trials.

Background: Pancreatic adenocarcinoma (PAC) has low overall survival (OS) rates and high recurrence rates following surgical resection. The role for preoperative radiation therapy (prRT) for PAC versus postoperative RT (poRT) remains uncertain. The authors used the National Cancer Data Base (NCDB) to report prRT outcomes for the largest multi-institutional patient cohort to date., Methods: NCDB data were obtained for all patients who underwent resection and external beam radiation (RT) for PAC from 1998 to 2002. Patients with metastatic (M1) disease, intraoperative RT, RT both before and after surgery, missing OS, or missing RT variables were excluded. Univariate (UV) and multivariate (MV) analysis were run using treatment characteristics, tumor characteristics, and patient demographics. The difference in patients' known characteristics was described by a chi-square test or analysis of variance., Results: A total of 5414 patients were identified. Of these, 277 received prRT and 5137 received poRT. Overall, 92.9% received chemotherapy and 7.1% received RT alone; 56% (2990 of 5307) of patients had stage III disease, according to American Joint Commission on Cancer (AJCC) staging manual, 5th edition. Median tumor size was 3 cm (range: 0-9.9 cm); 82% (199 of 244) of patients with prRT had negative surgical margins; 72% (3383 of 4699) of patients with poRT had negative margins. Forty-one percent (71 of 173) of patients with prRT were lymph node (LN)-positive; 65% (3159 of 4833) of patients with poRT were LN-positive. Median OS for patients with prRT was 18 months (95% CI = 18-19 months) and for patients with poRT, 19 months (95% CI = 17-22 months)., Conclusions: Receipt of prRT was associated with lower stage, higher rates of negative margins, and lower rates of lymph node positivity at resection. However, there was no significant difference in median OS versus that of the poRT group., (© 2013 American Cancer Society.)

Background: Mixed lineage kinase domain-like protein (MLKL) is a necrosome component mediating programmed necrosis that may be an important determinant of cancer cell death. The goal of the current study was to evaluate the prognostic value of MLKL expression in patients with pancreatic adenocarcinoma (PAC)., Methods: Tissue from 80 patients was collected from a prospectively maintained database of patients with PAC who underwent pancreaticoduodenectomy between January 2000 and October 2008. Immunohistochemistry analysis was performed and scored using an established scoring system. Kaplan-Meier survival curves were generated for recurrence-free survival (RFS) and overall survival (OS) for all patients and for patients receiving adjuvant chemotherapy. MLKL scores were correlated with RFS and OS using univariate and multivariate Cox regression analyses incorporating clinically relevant covariates., Results: The median age of the patients was 63 years and 53% were men. Low MLKL expression was associated with decreased OS (6 months vs 17 months; P = .006). In the subset of 59 patients who received adjuvant chemotherapy, low MLKL expression was associated with decreased RFS (5 months vs 15 months; P = .006) and decreased OS (6 months vs 19 months; P < .0001). On multivariate analysis, low MLKL expression was associated with poor OS in all patients (hazards ratio, 4.6 [95% confidence interval, 1.6-13.8]; P = .006) and in patients receiving adjuvant chemotherapy (hazards ratio, 8.1 [95% confidence interval, 2.2-29.2]; P = .002)., Conclusions: Low expression of MLKL is associated with decreased OS in patients with resected PAC and decreased RFS and OS in the subset of patients with resected PAC who receive adjuvant chemotherapy. The use of this biomarker in patients with PAC may provide important prognostic information., (Copyright © 2013 American Cancer Society.)

Background: Adjuvant radiotherapy (A-RT) for patients with resected pancreatic adenocarcinoma (PAC) is controversial. In the current study, the authors aim to determine whether there is an association between overall survival (OS) and A-RT dose., Methods: National Cancer Data Base (NCDB) data were obtained for all patients who received A-RT for resected PAC from 1998 through 2002. Univariate and multivariate survival analyses were performed along with Kaplan-Meier estimates for A-RT levels < 40 grays (Gy), 40 Gy to < 50 Gy, 50 Gy to < 55 Gy, and ≥ 55 Gy., Results: A total of 1385 patients met the inclusion criteria. The median age of the patients was 64 years (range, 29 years-87 years). All patients underwent surgical resection and A-RT with or without chemotherapy. A total of 231 patients were diagnosed with stage I disease, 273 were diagnosed with stage II disease, 734 were diagnosed with stage III disease, and 126 were diagnosed with stage IVA disease (according to the fifth edition of the American Joint Committee on Cancer); 21 were found to have an unknown stage of disease. The median A-RT dose was 45 Gy (range, 1.63 Gy-69 Gy). The median OS was 21 months (95% confidence interval [95% CI], 19 months-23 months). On multivariate analysis, an A-RT dose < 40 Gy (hazards ratio [HR], 1.30 [95% CI, 1.03-1.66]; P = .031), an A-RT dose of 40 Gy to < 50 Gy (HR, 1.17 [95% CI, 1.00-1.37]; P = .05), and an A-RT dose ≥ 55 Gy (HR, 1.44 [95% CI, 1.08-1.93]; P = .013) predicted worse OS compared with the reference category of 50 Gy to < 55 Gy., Conclusions: A-RT doses of < 40 Gy, 40 Gy to < 50 Gy, and ≥ 55 Gy were found to be associated with an inferior OS. The dose of A-RT delivered appears to influence OS and a prospective study evaluating the addition of optimally delivered A-RT for patients with resected PAC is needed., (Copyright © 2013 American Cancer Society.)